Disruption of IFN-I Signaling Promotes HER2/Neu Tumor Progression and Breast Cancer Stem Cells

作者：Castiello Luciano; Sestili Paola; Schiavoni Giovanna; Dattilo Rosanna; Monque Domenica M; Ciaffoni Fiorella; Iezzi Manuela; Lamolinara Alessia; Sistigu Antonella; Moschella Federica; Pacca Anna Maria; Macchia Daniele; Ferrantini Maria; Zeuner Ann; Biffoni Mauro; Proietti Enrico; Belardelli Filippo^*; Arico Eleonora^*

来源：Cancer Immunology Research, 2018, 6(6): 658-670.

DOI：10.1158/2326-6066.CIR-17-0675

Type I interferon (IFN-I) is a class of antiviral immunomodulatory cytokines involved in many stages of tumor initiation and progression. IFN-I acts directly on tumor cells to inhibit cell growth and indirectly by activating immune cells to mount antitumor responses. To understand the role of endogenous IFN-I in spontaneous, oncogene-driven carcinogenesis, we characterized tumors arising in HER2/neu transgenic (neuT) mice carrying a nonfunctional mutation in the IFNI receptor (IFNAR1). Such mice are unresponsive to this family of cytokines. Compared with parental neu(+/-) mice (neuT mice), IFNAR1(-/-) neu(+/-) mice (IFNAR-neuT mice) showed earlier onset and increased tumor multiplicity with marked vascularization. IFNAR-neuT tumors exhibited deregulation of genes having adverse prognostic value in breast cancer patients, including the breast cancer stem cell (BCSC) marker aldehyde dehydrogenase-1A1 (ALDH1A1). An increased number of BCSCs were observed in IFNAR-neuT tumors, as assessed by ALDH1A1 enzymatic activity, clonogenic assay, and tumorigenic capacity. In vitro exposure of neuT(+) mammospheres and cell lines to antibodies to IFN-I resulted in increased frequency of ALDH(+) cells, suggesting that IFN-I controls stemness in tumor cells. Altogether, these results reveal a role of IFN-I in neuT-driven spontaneous carcinogenesis through intrinsic control of BCSCs.

• 出版日期2018-6